Benefit of endovascular treatment for primary versus secondary medium vessel occlusion: A multi‐center experience

Abstract Aims This study aimed to compare the clinical outcomes and safety of endovascular treatment (EVT) in patients with primary versus secondary medium vessel occlusion (MeVO). Methods From the endovascular treatment for acute ischemic stroke in the China registry, we collected consecutive patients with MeVO who received EVT. The primary endpoint was a good outcome, defined as a modified Rankin Scale (mRS) 0 to 2 at 90 days. Results 154 patients were enrolled in the final analysis, including 74 primary MeVO and 80 secondary MeVO. A good outcome at 90 days was achieved in 42 (56.8%) patients with primary MeVO and 33 (41.3%) patients with secondary MeVO. There was a higher probability of good outcomes in patients with the primary vs secondary MeVO (adjusted odds ratio, 2.16; 95% confidence interval, 1.04 to 4.46; p = 0.04). There were no significant differences in secondary and safety outcomes between MeVO groups. In the multivariable analysis, baseline ASPECTS (p = 0.001), final modified thrombolysis in cerebral infarction score (p = 0.01), and any ICH (p = 0.03) were significantly associated with good outcomes in primary MeVO patients, while baseline National Institutes of Health Stroke Scale (p = 0.002), groin puncture to recanalization time (p = 0.02), and early neurological improvement (p < 0.001) were factors associated with good outcome in secondary MeVO patients. Conclusion In MeVO patients who received EVT, there was a higher likelihood of poor outcomes in patients with secondary versus primary MeVO.


| INTRODUC TI ON
Rapid recanalization to rescue ischemic penumbra is the cornerstone of achieving good outcomes in patients with acute ischemic stroke (AIS).Endovascular treatment (EVT) has been established as the standard care for patients with acute large vessel occlusion (LVO). 1,2However, the benefit of EVT for other vessel occlusions such as medium vessel occlusion (MeVO) is not clear.MeVO is usually defined as occlusion of middle cerebral artery (MCA) M2-M3 segments, anterior cerebral artery (ACA) A1-A3 segments, and posterior cerebral artery (PCA) P1-P3 segments, accounting for 25%-40% of acute cerebral vessel occlusions. 3Even in a distal occlusion location, the overall outcomes of MeVO receiving standard medical management is fair, with a third of patients not achieving functional independence at 3 months. 46][7] A multicenter study found that patients with MeVO and LVO achieved similar 90-day modified Rankin Scale (mRS), symptomatic intracranial hemorrhage (sICH) rate, and successful recanalization rate after EVT. 8 MeVO can involve a primarily isolated thrombus, a secondary distal or new territory embolism related to EVT, intravenous thrombolysis (IVT), or spontaneous migration. 91][12] Secondary MeVO caused by thrombectomy for LVO is not uncommon.One study observed that approximately 9.4% of thrombus escaped to the ACA during anterior circulation LVO thrombectomy, which was associated with increased mortality and disability. 13In clinical practice, many neurointerventionists choose to continue EVT when secondary MeVO occurs to seek complete recanalization, but the risks and benefits are not fully understood.Although EVT in distal occlusion may be safe and technically feasible, more thrombectomy passes may lead to blood-brain barrier disruption, resulting in greater sICH and poor outcomes. 14Meanwhile, secondary MeVO may have a larger ischemic territory than primary MeVO due to previous LVO.In this context, we speculate that the clinical outcome in patients with primary MeVO may be better than that in patients with secondary MeVO.Therefore, we conducted this retrospective study to compare the effectiveness and safety of EVT in patients with primary and secondary MeVO.

| Patients and design
We used data from the endovascular treatment for acute ischemic stroke in China (DETECT-China) registry, which was a retrospective, national, multi-center, registry study evaluating the efficacy and safety of patients suffering from LVO-AIS treated with EVT in 24 comprehensive stroke centers in China (NCT04752735).
The study was approved by the ethics committee of the General Hospital of Northern Theater Command (IRB: y (2021)013) and followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. 15Patient informed consent was waived due to the retrospective nature of this study.
We enrolled adult patients with anterior circulation AIS undergoing EVT from January 2018 to January 2023.The inclusion criteria were as follows: (1) evidence of primary isolated MeVO or secondary MeVO after thrombectomy of MCA-M1 occlusion; (2)   patients who received EVT, including stent retriever, aspiration, intra-arterial thrombolysis, rescue balloon or stenting angioplasty; and (3) mRS ≤ 2 before stroke onset.Patients with internal carotid artery occlusion, MCA-M1 occlusion, bilateral infarction, missing procedural details, premorbid mRS > 2, or mRS data missing were excluded from our study.

| Definition of MeVO
In this study, MeVO was confirmed by digital subtraction angiography (DSA) as occlusion of the M2, M3, A1, A2, or A3 segment, and categorized into primary and secondary etiologies. 9,16Primary MeVO refers to an isolated distal thrombus that developed de novo without severe stenosis or occlusion in proximal large vessels. 16,17Secondary MeVO arose from MCA-M1 occlusion, con-

| Outcomes
The primary endpoint was a good outcome, defined as mRS 0-2 at 90 days.Secondary endpoints included the proportion of patients with 90-day mRS 0-1 and 0-3, 90-day mRS distribution, early neurological improvement (ENI), and change in NIHSS score at 24 h, 48 h, 7 days, and at discharge.Safety endpoints were the proportion of sICH within 24 h, the proportion of any ICH within 24 h, and allcause mortality at 7 days and 90 days.ENI was defined as a decrease of more than 4 points in NIHSS score from baseline at 24 h, 18 and sICH was defined as an increase of more than 4 points in NIHSS score caused by ICH.

TA B L E 1 (Continued)
was no interaction effect of dominant and nondominant types in primary versus secondary M2 occlusion for all outcomes (all p interaction > 0.05).

| DISCUSS ION
In this study, we found that patients with primary MeVO had a higher probability of 90-day functional independence compared to those secondary MeVO.In addition, baseline ASPECTS, final mTICI 2b-3, and any ICH were significantly associated with good outcomes in primary MeVO, while baseline NIHSS, GTR, and ENI were factors or metrics associated with good outcomes in secondary MeVO.
Different type of M2 occlusion was not associated with primary versus secondary groups for all outcomes.
The clinical outcomes and safety of EVT for MeVO patients are not fully understood.IVT remains the first-line treatment recommended by international guidelines.0-1, with an early recanalization rate of less than 50% after IVT. 4 It is known that early recanalization is highly related to good prognosis, suggesting that medical treatment alone may not be the best option for MeVO patients.Across physician surveys, a growing number of interventionists would consider EVT for MeVO patients, particularly if they had not received preceding IVT. 16,20en a thrombus moves to a distal location, irreversible ischemic injury may have occurred in the blood supply area of the proximal occluded large vessels.Thus, a worse prognosis is expected to be observed in secondary MeVO compared with primary MeVO.The hypothesis was partially confirmed in this study because a greater proportion of primary MeVO patients achieved good outcomes than secondary patients.However, there was no difference in secondary outcomes between the two MeVO groups.This may be related to the relatively small sample size and heterogeneity of patients, for example, the high baseline NIHSS in the primary MeVO group.This further suggests a selection bias that primary MeVO patients with severe neurological deficits were more likely to receive EVT. 21 In addition, most confirmation of MeVO in this study depended on DSA; however, there was a possibility of large vessel thrombus migrating to a more distal vessel, 17 resulting in the fact that some patients with secondary MeVO might have been mixed in the primary MeVO group.These factors may affect the outcome of primary MeVO.
ICH is a common complication of EVT. 22The small diameter, fragile wall, and tortuous access pathways of medium-sized vessels undoubtedly increase the technical difficulty of EVT.In our study, the incidence of ICH in the MeVO group was high (34.0%),and was more significant in the secondary MeVO, with up to 41.8% rate of ICH (of which, 19.0% were sICH).Given the poor performance of non-contrast CT to detect small infarcts, it was probable that EVT was performed for MeVO in which the blood-supply area was already infarcted, which may partially explain the higher ICH rate.Furthermore, more severe endothelium injury 23 and mechanical blood-brain barrier disruption 14 caused by frequent MT passes could be another reason for the higher incidence of ICH in secondary MeVO.Interestingly, compared with LVO patients in the HERMES collaboration, 24 we found that the patients with secondary MeVO had a higher incidence of atrial fibrillation (50% vs. 33%).Of note, cardiogenic emboli may be a risk factor for ICH due to secondary embolism during EVT. 25 All patients who died in the primary MeVO group had sICH, with the mortality event occurring within 7 days.This suggests that ICH occurring during the procedure may be at high risk of mortality in patients with MeVO.These results suggest that interventionists should balance the benefits and risks to carefully choose treatment strategies.7][28][29] In addition, general anesthesia can reduce patient movement and agitation, making it easier for the guide wire or catheter to reach the distal vessels, which may improve the safety of EVT for MeVO. 9Nevertheless, for secondary MeVO, switching anesthesia methods during the procedure would not be the choice of most physicians. 30e baseline ASPECTS has been a strong predictor of functional outcome in AIS, 31 which was also observed in primary MeVO in this study.It is widely accepted that successful recanalization is associated with good outcomes after EVT. 32However, the rate of final mTICI sisting of three instances: (1) distal or new territory MeVO after EVT; (2) IVT-induced or spontaneous thrombus migration, defined as MCA-M1 occlusion at baseline confirmed by CT angiography, which was found as MeVO by preprocedural DSA; (3) MeVO located at the distal position of MCA-M1 with severe stenosis or occlusion.

2. 3 |
Data collectionPatient demographics, medical history, National Institutes of Health Stroke Scale (NIHSS), imaging data, procedural details, and laboratory indexes were collected.The imaging data, including baseline Alberta Stroke Program Early CT Score (ASPECTS), occlusion site, and postprocedural intracranial hemorrhage (ICH), were evaluated by a neuroradiologist.If the CT image was not of adequate quality to assign an ASPECTS or if there was a lack of CT imaging at admission (due to transfer patients), it was recorded as missing.The preprocedural collateral status and postprocedural mTICI grading were evaluated by a neurologist during the procedure and recorded in the medical record.If there were no relevant records, the data were obtained by a neurologist who read these images.We recorded procedure complications, including target vessel perforation, dissection, and vasospasm.The 90-day mRS score was evaluated through telephone interviews or in-person follow-up.

2. 5 |
Statistical analysis SPSS V.25.0 software was used to conduct the statistical analyses.Shapiro-Wilk test was used to assess data distribution.Continuous variables were presented as mean ± SD or median (IQR), and compared with t-test or Mann-Whitney U-test depending on their normality.Categorical variables were described using numbers (percentage) and compared between groups via Pearson's χ 2 test or Fisher's exact test as appropriate.To compare the functional outcomes of primary MeVO and secondary MeVO, we performed binary and ordinal logistic regression models to evaluate the 90-day mRS and its distribution, sICH, and any ICH.A generalized linear model was used to analyze the change in NIHSS score, and Cox regression analysis was used to analyze all-cause mortality.We adjusted for confounding factors a priori that are known to affect patient outcomes, such as age, gender, baseline NIHSS, pretreatment with IVT, pre-stroke mRS, onset to puncture time (OTP), groin puncture to recanalization time (GTR), preprocedural collateral, and final mTICI.Next, the MeVO population was divided into the good outcome and poor outcome groups.Univariable logistic regression analysis was conducted.Variables with p < 0.05 were identified as potential predictors.The variance inflation factor (VIF) was used to evaluate their multicollinearity (VIF < 3 was considered non-collinearity), and qualified variables were included in a stepwise logistic regression model to analyze independent factors associated with a 90-day good outcome.We also performed a subgroup analysis regarding outcomes of different M2 occlusion types (dominant or nondominant) in the primary versus secondary group with interaction test, and adjusted for age, baseline NIHSS, pretreatment with IVT, and final mTICI.All statistical tests were two-sided, with p < 0.05 considered statistically significant.

| 7 of 10 HU
Abbreviations: CI, confidence interval; cOR, common odds ratio; ENI, early neurological improvement; GMR, geometric mean ratio; HR, hazard ratio; ICH, intracranial hemorrhage; MeVO, medium vessel occlusion; mRS, modified Rankin Scale; NIHSS, National Institute of Health Stroke Scale; OR, odds ratio; SICH, symptomatic intracranial hemorrhage.a Adjusted for key prognostic covariates (age, sex, pre-treatment with IVT, pre-stroke mRS, baseline NIHSS, OTP, GTR, LMC and final mTICI).b Calculated with ordinal regression analysis.c The log (NIHSS + 1) was analyzed using a generalized linear model.d Calculated with Cox regression model.e Two missing data.f Nine missing data.g Nineteen missing data.
Study flowchart of patient enrollment.AIS, acute ischemic stroke; ICA, internal carotid artery; LVO, large vessel occlusion; MCA-M1, middle cerebral artery M1 segment; MeVO, medium vessel occlusion; mRS, modified Rankin Scale.Baseline characteristics and outcome of patients with primary and secondary MeVO.
Efficacy and safety outcome in patients with primary and secondary MeVO.
1 However, a post hoc analysis of INTERRSeCT and PRoveIT showed that only half of MeVO patients receiving the best medical treatment achieved 90-day mRS TA B L E 2 Note: Bold values indicate statistical significance.

TA B L E 3
Univariate and multivariable analyses regarding good and poor outcomes of all MeVO patients.Alberta Stroke Program Early CT Score; GTR, groin puncture to recanalization time; MeVO, medium vessel occlusion; MT, mechanical thrombectomy; mTICI, modified thrombolysis in cerebral infarction score; NIHSS, National Institute of Health Stroke Scale; NLR, neutrophil-to-lymphocyte ratio.Univariable and multivariable analyses regarding good and poor outcomes in patients with medium vessel occlusion (MeVO).Bold values indicate statistical significance in multivariable analysis.Abbreviations: ASPECTS, Alberta Stroke Program Early CT Score; GTR, groin puncture to recanalization time; mTICI, modified thrombolysis in cerebral infarction score; NIHSS, National Institute of Health Stroke Scale; NLR, neutrophil-to-lymphocyte ratio.
a Only variables with p < 0.05 in univariable logistic regression are listed.b Calculated with stepwise logistic regression model.c Eight missing data.d One missing data.TA B L E 4 a Only variables with p < 0.05 in univariable logistic regression are listed.b Calculated with stepwise logistic regression model.c Six missing data.d Two missing data.e One missing data.